Blue dyes in medicine – a confusing terminology

Dear Sir, Lymphatic mapping and sentinel lymph node biopsy with blue dyes are routinely used for staging of patients with breast cancer and other malignant tumours. With increasing use of this technique, studies and reports of adverse effects have become more frequent, most commonly regarding anaphylactic reactions to the dyes used for lymphatic mapping. Although it is very important to raise awareness and collect data of adverse events, many recent publications, among them also the latest on this topic in this journal (1), suffer from some inaccuracies that are in part due to complicated systematics of the dyes and a misleading terminology even in the chemical literature (2). As the authors correctly state, there is a strong cross-reactivity between Patent Blue V (calciumchelated dimer: CAS number: 3536-49-0) and Isosulfan Blue (CAS number: 68238-36-8). Both belong to the group of triarylmethan dyes and basically share the same formula; however, Patent Blue V has an additional hydroxyl group at position 5. Isosulfan Blue is the structural isomer of Patent Blue VF (CAS number: 129-17-9, not Patent Blue V) (2) (Fig. 1). Patent Blue V, not Patent Blue VF, is also used as food colourant with the number E 131 and is still on the market as such, in contrast to several reports (1, 3) (Table 1). Methylene blue [CAS number: 61-73-4 (anhydrous methylene blue), CAS number: 7220-79-3 (methylene blue trihydrate)] is sometimes mentioned as another dye successfully used for lymphatic mapping (1, 4, 5). It is also approved for oral or intravenous administration for the treatment of methemoglobinaemia and haemolysis, but maximal doses should be respected because of its systemic toxicity. If used locally, it should be deeply injected, since it may cause severe necrosis upon intradermal administration (6). According to Tsopelas and Sutton (7), however, methylene blue does not bind to plasma proteins, having no sulfonic acid groups, and is therefore not taken up by lymph but diffuses directly into blood capillaries, which may limit its use as agent for lymphatic mapping. An immunoglobulin E (IgE)-mediated mechanism was recently demonstrated by Woehrl et al. (8) in patients with prior anaphylactic reactions to Isosulfan Blue, although previous publications suggested pseudoallergic mechanisms. Determination of specific IgE to both dyes may be attempted by the commercial ImmunoCAP method (Pharmacia Diagnostics, Uppsala, Sweden). Given the relatively small molecular weight of Isosulfan Blue and Patent Blue V, theses dyes are very likely to act as haptens. This may influence the sensitivity of in vitro tests, which are based on detection of complete antigens. It is important to publish reports on adverse events from a technique with widespread use. However, a strong emphasis should be put on the correct terminology to avoid misleading or even dangerous statements. Therefore, we strongly recommend the use of CAS or CI numbers (9) to unambiguously identify the dyes.